CN107050455A - 用于治疗中枢介导的恶心及呕吐的组合物及方法 - Google Patents
用于治疗中枢介导的恶心及呕吐的组合物及方法 Download PDFInfo
- Publication number
- CN107050455A CN107050455A CN201610795817.1A CN201610795817A CN107050455A CN 107050455 A CN107050455 A CN 107050455A CN 201610795817 A CN201610795817 A CN 201610795817A CN 107050455 A CN107050455 A CN 107050455A
- Authority
- CN
- China
- Prior art keywords
- vomiting
- nausea
- netupitant
- palonosetron
- day
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010047700 Vomiting Diseases 0.000 title claims abstract description 116
- 230000008673 vomiting Effects 0.000 title claims abstract description 96
- 206010028813 Nausea Diseases 0.000 title claims abstract description 55
- 239000000203 mixture Substances 0.000 title claims abstract description 50
- 230000008693 nausea Effects 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002512 chemotherapy Methods 0.000 claims abstract description 28
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 claims description 93
- 229960005163 netupitant Drugs 0.000 claims description 91
- 229960002131 palonosetron Drugs 0.000 claims description 77
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 claims description 77
- 238000011282 treatment Methods 0.000 claims description 56
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 40
- 229960003957 dexamethasone Drugs 0.000 claims description 40
- 239000002775 capsule Substances 0.000 claims description 33
- 238000009472 formulation Methods 0.000 claims description 27
- 230000001154 acute effect Effects 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 20
- 239000000370 acceptor Substances 0.000 claims description 18
- 239000005557 antagonist Substances 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 claims description 15
- 239000002552 dosage form Substances 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 12
- 229940002612 prodrug Drugs 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims description 7
- 230000008499 blood brain barrier function Effects 0.000 claims description 6
- 210000001218 blood-brain barrier Anatomy 0.000 claims description 6
- 229940049706 benzodiazepine Drugs 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 229940100691 oral capsule Drugs 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 abstract description 4
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 24
- 229960001372 aprepitant Drugs 0.000 description 23
- 239000003814 drug Substances 0.000 description 17
- 239000000499 gel Substances 0.000 description 17
- 230000006698 induction Effects 0.000 description 16
- 201000010099 disease Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000945 filler Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 239000010977 jade Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229960005343 ondansetron Drugs 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- -1 dexamethasone Chemical class 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001839 systemic circulation Effects 0.000 description 4
- 210000004916 vomit Anatomy 0.000 description 4
- QBADKJRRVGKRHP-JLXQGRKUSA-N (3as)-2-[(3s)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3h-benzo[de]isoquinolin-1-one;2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethyl-n-[6-(4-methylpiperazin-1-yl)-4-[(3z)-penta-1,3-dien-3-yl]pyridin-3-yl]propanamide Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1.C\C=C(\C=C)C1=CC(N2CCN(C)CC2)=NC=C1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 QBADKJRRVGKRHP-JLXQGRKUSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229940014259 gelatin Drugs 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- CCIWVEMVBWEMCY-RCFOMQFPSA-N (2s)-1-[(3as,4s,7as)-4-hydroxy-4-(2-methoxyphenyl)-7,7-diphenyl-1,3,3a,5,6,7a-hexahydroisoindol-2-yl]-2-(2-methoxyphenyl)propan-1-one Chemical compound COC1=CC=CC=C1[C@H](C)C(=O)N1C[C@H](C(CC[C@@]2(O)C=3C(=CC=CC=3)OC)(C=3C=CC=CC=3)C=3C=CC=CC=3)[C@H]2C1 CCIWVEMVBWEMCY-RCFOMQFPSA-N 0.000 description 2
- XILNRORTJVDYRH-HKUYNNGSSA-N (2s,3s)-n-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound C1([C@@H]2NCCC[C@@H]2NCC2=CC(=CC=C2OC)N2C(=NN=N2)C(F)(F)F)=CC=CC=C1 XILNRORTJVDYRH-HKUYNNGSSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229910003978 SiClx Inorganic materials 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037058 blood plasma level Effects 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229950007605 dapitant Drugs 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229960003413 dolasetron Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 239000007897 gelcap Substances 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 2
- 229960003727 granisetron Drugs 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229950005286 lanepitant Drugs 0.000 description 2
- 238000007477 logistic regression Methods 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229960004503 metoclopramide Drugs 0.000 description 2
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- CVXJAPZTZWLRBP-MUUNZHRXSA-N n-[(2r)-1-[acetyl-[(2-methoxyphenyl)methyl]amino]-3-(1h-indol-3-yl)propan-2-yl]-2-(4-piperidin-1-ylpiperidin-1-yl)acetamide Chemical compound COC1=CC=CC=C1CN(C(C)=O)C[C@H](NC(=O)CN1CCC(CC1)N1CCCCC1)CC1=CNC2=CC=CC=C12 CVXJAPZTZWLRBP-MUUNZHRXSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 229950005485 vofopitant Drugs 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- XWNBGDJPEXZSQM-VZOBGQTKSA-N (2r,4s)-4-[(8as)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-n-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-n-methylpiperidine-1-carboxamide Chemical compound C1([C@H]2C[C@H](CCN2C(=O)N(C)[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)N2C[C@H]3N(C(CC3)=O)CC2)=CC=C(F)C=C1C XWNBGDJPEXZSQM-VZOBGQTKSA-N 0.000 description 1
- SBBYBXSFWOLDDG-JLTOFOAXSA-N (2s)-n-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-n-methylpiperazine-1-carboxamide Chemical compound C1([C@H]2CNCCN2C(=O)N(C)[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=CC=C(F)C=C1C SBBYBXSFWOLDDG-JLTOFOAXSA-N 0.000 description 1
- LDXQLWNPGRANTO-GOSISDBHSA-N (9r)-7-[[3,5-bis(trifluoromethyl)phenyl]methyl]-9-methyl-5-(4-methylphenyl)-8,9,10,11-tetrahydro-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione Chemical compound C([C@H](CN(CC=1C=C(C=C(C=1)C(F)(F)F)C(F)(F)F)C1=O)C)CN(C(C2=NC=CC=C22)=O)C1=C2C1=CC=C(C)C=C1 LDXQLWNPGRANTO-GOSISDBHSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYDFXSRVZBYYJV-TYYBGVCCSA-N (e)-but-2-enedioic acid;sodium Chemical compound [Na].OC(=O)\C=C\C(O)=O RYDFXSRVZBYYJV-TYYBGVCCSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical class CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- RPDFDSQFBCJTDY-GAQXSTBRSA-N 1-[(3s)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]octan-1-yl)ethyl]piperidin-1-yl]-2-(3-propan-2-yloxyphenyl)ethanone Chemical compound CC(C)OC1=CC=CC(CC(=O)N2C[C@](CC[N+]34CCC(CC3)(CC4)C=3C=CC=CC=3)(CCC2)C=2C=C(Cl)C(Cl)=CC=2)=C1 RPDFDSQFBCJTDY-GAQXSTBRSA-N 0.000 description 1
- BTQZKHUEUDPRST-UHFFFAOYSA-N 1-fluoro-3-methylbenzene Chemical class CC1=CC=CC(F)=C1 BTQZKHUEUDPRST-UHFFFAOYSA-N 0.000 description 1
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 1
- NCPKXVSLLSEPDP-UHFFFAOYSA-N 2-(4-acetylpiperazin-1-yl)-6-[[3,5-bis(trifluoromethyl)phenyl]methyl]-4-(2-methylphenyl)-8,9-dihydro-7h-pyrimido[4,5-b][1,5]oxazocin-5-one Chemical compound C1CN(C(=O)C)CCN1C(N=C1C=2C(=CC=CC=2)C)=NC2=C1C(=O)N(CC=1C=C(C=C(C=1)C(F)(F)F)C(F)(F)F)CCCO2 NCPKXVSLLSEPDP-UHFFFAOYSA-N 0.000 description 1
- ZLNYUCXXSDDIFU-LJAQVGFWSA-N 2-[1-[2-[(2r)-4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]piperidin-4-yl]-2-methylpropanamide Chemical compound C1CC(C(C)(C)C(N)=O)CCN1CC[C@]1(C=2C=C(Cl)C(Cl)=CC=2)OCCN(C(=O)CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C1 ZLNYUCXXSDDIFU-LJAQVGFWSA-N 0.000 description 1
- ZGNPLCMMVKCTHM-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethyl-n-[4-(2-methylphenyl)-6-morpholin-4-ylpyridin-3-yl]propanamide Chemical compound C=1N=C(N2CCOCC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZGNPLCMMVKCTHM-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 206010066091 Bronchial Hyperreactivity Diseases 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 230000001062 anti-nausea Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229950006529 befetupitant Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 230000036427 bronchial hyperreactivity Effects 0.000 description 1
- 230000010083 bronchial hyperresponsiveness Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- XGGTZCKQRWXCHW-WMTVXVAQSA-N casopitant Chemical compound C1([C@H]2C[C@H](CCN2C(=O)N(C)[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)N2CCN(CC2)C(C)=O)=CC=C(F)C=C1C XGGTZCKQRWXCHW-WMTVXVAQSA-N 0.000 description 1
- 229960003778 casopitant Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000004326 gyrus cinguli Anatomy 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- IYRMNDOLPONSCJ-UHFFFAOYSA-N isoquinolin-2-ium;chloride Chemical compound Cl.C1=NC=CC2=CC=CC=C21 IYRMNDOLPONSCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- KJBLQGHJOCAOJP-UHFFFAOYSA-N metoclopramide hydrochloride Chemical compound O.Cl.CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC KJBLQGHJOCAOJP-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- NXLUTEDAEFXMQR-BJKOFHAPSA-N n-[(2r,4s)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-chlorophenyl)methyl]piperidin-4-yl]quinoline-4-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2[C@@H](C[C@H](CC2)NC(=O)C=2C3=CC=CC=C3N=CC=2)CC=2C=CC(Cl)=CC=2)=C1 NXLUTEDAEFXMQR-BJKOFHAPSA-N 0.000 description 1
- BHCJHYIMNHXLOM-WVDRJWPYSA-N n-[(e,2r)-1-(3,4-dichlorophenyl)-5-oxo-5-[[(3r)-2-oxoazepan-3-yl]amino]pent-3-en-2-yl]-n-methyl-3,5-bis(trifluoromethyl)benzamide Chemical compound C([C@@H](N(C)C(=O)C=1C=C(C=C(C=1)C(F)(F)F)C(F)(F)F)\C=C\C(=O)N[C@H]1C(NCCCC1)=O)C1=CC=C(Cl)C(Cl)=C1 BHCJHYIMNHXLOM-WVDRJWPYSA-N 0.000 description 1
- 229940029320 netupitant 300 mg Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229950006784 orvepitant Drugs 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 229940024224 palonosetron 0.5 mg Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- FIVSJYGQAIEMOC-ZGNKEGEESA-N rolapitant Chemical compound C([C@@](NC1)(CO[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=CC=CC=2)C[C@@]21CCC(=O)N2 FIVSJYGQAIEMOC-ZGNKEGEESA-N 0.000 description 1
- 229960001068 rolapitant Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- 229950007305 vestipitant Drugs 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Paints Or Removers (AREA)
- Medicines Containing Plant Substances (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了用于治疗或预防正接受化疗、放疗或外科手术的患者的恶心及呕吐的组合物及方法。
Description
本申请是申请日为2010年11月18日、申请号为201080052107.0、名称为“用于治疗中枢介导的恶心及呕吐的组合物及方法”的发明申请的分案。
相关申请的交叉引用
本申请要求于2009年11月18日提交的美国临时申请61/262,470以及于2010年9月4日提交的美国临时申请61/382,709的优先权。申请61/262,470以及61/382,709以引用的方式全文纳入本文。
技术领域
本发明涉及中枢作用NK1拮抗剂治疗恶心及呕吐,特别是由高度致呕吐性化疗诱发的恶心及呕吐,的用途;以及涉及对连续多日所述恶心及呕吐的治疗。本发明还涉及帕洛诺司琼(palonosetron)与奈妥匹坦(netupitant)的结合口服剂型。
背景技术
20世纪90年代早期,随着5-HT3拮抗剂的开发,医疗机构中出现了新方法以更好地控制由各种医疗过程造成的恶心及呕吐,包括化疗造成的恶心及呕吐(CINV)、术后恶心及呕吐(PONV)以及放疗造成的恶心及呕吐(RINV)。当加入类固醇如地塞米松中时,若干5-HT3拮抗剂显示出显著提高正在经受致呕吐性医疗过程的患者的生活水平。5-HT3拮抗剂的实例包括葛兰素史克公司(GlaxosmithKline)销售的昂丹司琼(ondansetron)以及海尔森保健公司(Helsinn Healthcare)开发的帕洛诺司琼。
最近,盐酸帕洛诺司琼开始作为高效抗恶心剂及抗呕吐剂。参见海尔森保健公司的PCT公开文本WO 2004/045615和WO 2004/073714。盐酸帕洛诺司琼在美国作为商标为的无菌注射液出售,形式为含有0.075或0.25mg盐酸帕洛诺司琼的无菌单位剂量小瓶。盐酸帕洛诺司琼也以口服给药的含有0.5mg盐酸帕洛诺司琼的软凝胶剂型出售。
盐酸帕洛诺司琼的正式名称为(3aS)-2-[(S)-1-氮杂双环[2.2.2]辛-3-基]-2,3,3a,4,5,6-六氢-1-氧代-1H-苯并[de]异喹啉盐酸盐(CAS编号119904-90-4);其经验式为C19H24N2O·HCl,分子量为332.87。所述化合物表示为以下化学结构:
合成帕洛诺司琼的方法描述于美国专利5,202,333和5,510,486。可药用剂型描述于海尔森保健公司的PCT公开文本WO 2004/067005和WO 2008/049552。
近来,NK1拮抗剂也已经开始作为对抗由致呕吐性医疗过程诱发的恶心及呕吐的工具。最近,食品药物管理局(“FDA”)批准了阿瑞匹坦(aprepitant)用于与其他抗呕吐剂的结合物以预防由中度及高度致呕吐性化疗诱发的恶心及呕吐。然而,很快发现,阿瑞匹坦的效果主要限于呕吐——而对恶心无效——并且阿瑞匹坦在CINV急性期效果不大。当测试对抗人的恶心时,与单独使用5-HT3拮抗剂相比,阿瑞匹坦不能导致中度或高度致呕吐性化疗后恶心的发生率及严重性的显著下降。参见FDA批准的的标签。因此,虽然FDA批准阿瑞匹坦用于预防人类的恶心及呕吐,但是这一标识具有某种程度的误导,因为在对阿瑞匹坦进行的临床试验中,阿瑞匹坦减轻恶心的程度并不比其他给药方案的抗呕吐成分的减轻程度更高。此外,Grunberg等人于SUPPORT CANCER CARE 2009年第17卷第589至594页报导的阿瑞匹坦与帕洛诺司琼的结合治疗的结果与预计的相差甚远。
默克公司(Merck Co.)在美国以为商标销售阿瑞匹坦。产品被批准为胶囊剂型,并销售以用于与其他抗呕吐剂如昂丹司琼及灭吐灵(metoclopramide)结合使用以预防CINV(急性及迟发性)。该产品据报道具有9至13小时的终末半衰期。尽管阿瑞匹坦已经显示出某些抗恶心效果,然而其效果并不一致。卡索匹坦(casopitant)是另一种已经测试对抗人的恶心及呕吐的NK1拮抗剂。Ruhlmanne等人于Therapeutics and Clinical RiskManagement 2009年第5期第375页至第384页中,以及Pellegatti等人于Drug Metabolismand Dispositon 2009年第37卷第8期第1635页至第1645页中探讨了卡索匹坦的临床研究。如Ruhlmanne等人于Therapeutics and Clinical Risk Management 2009年第5期第375页至第384页中所报导的,当对于中度致呕吐性化疗给药时,卡索匹坦并无令人满意的显著抗恶心效果,甚至具有诱发恶心的负作用。卡索匹坦为(2R,4S)-4-(4-乙酰基哌嗪-1-基)-N-{(1R)-1-[3,5-双(三氟甲基)苯基]乙基}-2-(4-氟-2-甲基苯基)-N-甲基哌啶-1-甲酰胺,并具有以下化学结构:
奈妥匹坦(netupitant)是海尔森保健公司开发的另一种选择性NK1受体拮抗剂,具有式2-[3,5-双(三氟甲基)苯基]-N,2-二甲基-N-[4-(2-甲基苯基)-6-(4-甲基哌嗪-1-基)吡啶-3-基]丙酰胺,或N,α,α-三甲基-N-[4-(2-甲基苯基)-6-(4-甲基-1-哌嗪基)-3-吡啶基]-3,5-双(三氟甲基)-苯乙酰胺,和以下的化学结构:
合成及配制奈妥匹坦及其前药的方法描述于霍夫曼-罗氏公司(Hoffanne LaRoche)的美国专利6,297,375、6,719,996和6,593,472中。
其他代表性NK1拮抗剂包括ZD4974(由阿斯利康公司(AstraZeneca)开发)、CGP49823(由汽巴-嘉基公司(Ciba-Geigy)开发)、拉奈匹坦(Lanepitant)及LY686017(由礼来公司(Eli Lilly)开发)、FK888(由藤泽公司(Fujisawa)开发)、沃氟匹坦(Vofopitant)、维替匹坦(Vestipitant)及奥维匹坦(Orvepitant)(由葛兰素史克公司开发)、贝非匹坦(Befetupitant)(由霍夫曼-罗氏公司开发)、R116031(由杨森公司(Janssen)开发)、L-733060及L-736281(由默克公司开发)、TKA731、NKP608及DNK333(由诺华公司(Novartis)开发)、CP-96345、CP-99994、CP-122721、CJ-17493、CJ-11974及CJ-11972(由辉瑞公司(Pfizer)开发)、RP67580及达匹坦(Dapitant)(由罗讷乐安公司(Rhone-Poulenc Rorer)开发)、诺匹坦铵(Nolpitantium)及SSR240600(由赛诺菲-安万特公司(Sanofi-Aventis)开发)、SCH388714及罗拉匹坦(Rolapitant)(由先灵葆雅公司(Schering-Plough)开发)、TAK637(由武田公司(Takeda)开发),HSP117(由久光公司(Hisamitsu)开发)、KRP103(由杏林制药(Kyorin Pharm)开发)及SLV317(由苏威公司(Solvay)开发)。上述NK1拮抗剂的化学结构如下所示,黄(Huang)等人于Expert Opin.Ther.Patents 2010年第20卷第8期第1019页至第1045页中探讨了这些化合物以及其他NK1拮抗剂。
美国专利6,297,375的背景技术表明,NK1拮抗剂对于治疗物质P(NK1受体的天然配体)有活性的多种病症有帮助。这些病症包括抑郁、疼痛(尤其是炎症,如偏头痛、类风湿性关节炎、哮喘及炎性肠病,引起的疼痛)、中枢神经系统(CNS)病症(例如帕金森症和阿兹海默症)、头痛、焦虑症、多发性硬化、吗啡戒断衰减、心血管病变、水肿、慢性炎症(如类风湿性关节炎)、哮喘/支气管高反应性(bronchial hyperreactivity)及其他呼吸系统疾病(包括变应性鼻炎、肠的炎症包括溃疡性结肠炎及克隆氏病(Crohn's disease))、眼外伤及眼部炎症。所述背景技术甚至提及晕动症及呕吐,但没有具体提及恶心。
因此,本领域需要对于恶心及呕吐,特别是化疗、放疗及外科手术诱发的恶心及呕吐,的更有效的治疗。此外,如果由所述致呕吐性事件诱发的恶心及呕吐的发生延长,还需要在更长时间中治疗所述恶心及呕吐。再者,还需要开发剂型以降低药物与药物的相互作用、提高稳定性、以及增强组合剂型的每种组分的效果。
发明目标
因此,本发明的一个目标是提供使用NK1拮抗剂,特别是奈妥匹坦,治疗或预防恶心及呕吐的新方法。
本发明的另一目标是提供治疗或预防正在接受化疗、放疗或外科手术的患者的恶心及呕吐的方法。
本发明的又一目标是放大现有的通过类固醇及5-HT3拮抗剂对CINV、RINV或PONV的治疗,并藉此,尤其在急性及延迟期内,提供对抗恶心及呕吐两者的额外保护。
本发明的另一目标是提供奈妥匹坦与5-HT3拮抗剂的单次结合给药,以及该单次给药无需再次给药用于治疗CINV、RINV或PONV的急性及延迟期内的恶心及呕吐的用途。
另一目标是提供在中度致呕吐性及高度致呕吐性化疗(“MEC及HEC”),特别是HEC,后的急性及延迟期内,治疗由这些治疗引起的恶心、呕吐及其他不想要的效应的新方法。
另一目标是提供新剂型,以在对恶心及呕吐的治疗或预防中对包含奈妥匹坦和/或5-HT3拮抗剂和/或地塞米松的结合剂型降低药物与药物相互作应、改善稳定性、提高生物可利用性并增强每种组分的疗效。
发明内容
对奈妥匹坦的临床效果进行大量测试之后,出乎意料地发现奈妥匹坦具有对抗恶心的活性,并且奈妥匹坦的单次给药能够连续五天治疗由高度及中度致呕吐性化疗引起的恶心及呕吐。已经发现,非常出乎意料地,奈妥匹坦显示出与脑中NK1受体的独特结合习性。具体地,以及发现奈妥匹坦以长时程的方式结合纹状体中的NK1受体,甚至在给药后96小时,仅少于20%或30%的奈妥匹坦自纹状体NK1受体释放。这与阿瑞匹坦形成鲜明对比,后者中的受体结合随时间急剧下降,如果需要在整个延迟期内控制呕吐,则必须重复给药;而且阿瑞匹坦没有显示出显著的抗恶心效果。
这些发现已经导致开发独特的给药方案,以在呕吐诱发事件后的第一天,以及此诱发后的第二天、第三天、第四天及第五天中治疗恶心。因此,在一个实施方案中,本发明提供了一种在需要治疗的患者中连续五天治疗恶心及呕吐的方法,该方法包括对该患者给予奈妥匹坦或其可药用盐,其量对急性及延迟期的恶心及呕吐可有效治疗,并且可有效进入全身循环系统,跨越血脑屏障,并在所述给药后72小时占据纹状体中至少70%的NK1受体。
在另一实施方案中,将奈妥匹坦与其他抗呕吐剂——包括5-HT3拮抗剂如帕洛诺司琼以及皮质类固醇如地塞米松——以达到甚至更高抗恶心效果的方式结合。已经发现,如Grunberg等人于Support Cancer Care(2009)17:589-594中所报导的,帕洛诺司琼在与奈妥匹坦的结合物中比在与阿瑞匹坦的结合物中更有效。此外,与单独给予帕洛诺司琼相反,当帕洛诺司琼与奈妥匹坦结合使用时,帕洛诺司琼显示出改善的药代动力学谱(如更好的生物可利用性)。基于这些发现,已经开发了固体口服剂型,其将奈妥匹坦或另一种NK1拮抗剂与帕洛诺司琼结合用于治疗急性及延发性呕吐。
还已经发现,奈妥匹坦可增强地塞米松的效果,使得甚至当以低于治疗剂量(即,若单独给予地塞米松无效的剂量)给药时,地塞米松有效。因此,在另一实施方案中,本发明提供了在需要治疗的患者中连续五天治疗恶心及呕吐的结合疗法,主要由下述组成:
第一天,奈妥匹坦:于第一天对该患者给予奈妥匹坦或其可药用盐,其量对急性及延迟期的恶心及呕吐可有效治疗,并且可有效进入全身循环系统,跨越血脑屏障,并在给药后72小时占据纹状体中至少70%的NK1受体;
第一天,帕洛诺司琼:于第一天对该患者给予可有效治疗所述急性及延迟期的恶心及呕吐的治疗有效量的5-HT3拮抗剂(优选帕洛诺司琼);
第一天,地塞米松:于第一天对该患者给予当单独给药时对恶心及呕吐无效,但当与所述奈妥匹坦及帕洛诺司琼结合给药时对恶心及呕吐有效的第一剂地塞米松,其中所述第一剂包含单独给药时最小有效剂量的50至70%;以及
第二至五天,地塞米松:当该患者正接受高度致呕吐性化疗时,于第二天、第三天及第四天对该患者给予当单独给药时对恶心及呕吐无效,但当与所述奈妥匹坦结合给药时对恶心及呕吐有效的第二剂地塞米松,其中在第二天、第三天及第四天所述第二剂包含单独给药时最小有效剂量的40至60%。
由于统一的设计及配制,所述剂型非常地通用和稳定。通过将所述NK1拮抗剂与帕洛诺司琼配制在分开的剂型中并将所述剂型组合在一个胶囊中来实现该通用性及稳定性。因此,例如,可将帕洛诺司琼以约0.5mg的剂量配制于小凝胶帽中,并可将奈妥匹坦或其他NK1拮抗剂以约100至150mg的剂量配制在片剂中。随后,基于该产品的治疗目的,可将一个或多个帕洛诺司琼凝胶帽及一个或多个奈妥匹坦(或其他NK1拮抗剂)片填入胶囊中。因为帕洛诺司琼及NK1拮抗剂处于分开的剂量单元中,它们可被配制而无需顾及另一成分的稳定性,并且不会降解为副产物,如帕洛诺司琼的一种降解副产物(3S)-3-[(3aS)-1-氧代-2,3,3a,4,5,6-六氢-1H-苯并[de]异喹啉-2-基]-1-氮杂双环[2.2.2]辛-1-酸酯。因此,本发明发现的剂型具有优势,例如在治疗或预防呕吐中降低药物与药物相互作应、改善稳定性以及增强所述剂型中每种成分的效果。
因此,在一个实施方案中,本发明提供了包含帕洛诺司琼与NK1拮抗剂(优选奈妥匹坦)或其可药用盐或前药的口服给药剂型。
在另一个实施方案中,本发明提供了包含以下的口服给药胶囊剂型:(a)外壳;(b)一个或多个封装于该外壳内的片剂,各自均包含NK1拮抗剂(优选奈妥匹坦)或其可药用盐或前药以及一种或多种可药用赋形剂;以及(c)一个或多个封装于该外壳内的软凝胶胶囊,各自均包含帕洛诺司琼或其可药用酯或前药以及一种或多种可药用的赋形剂;其中所述剂型以不超过3wt.%的量包含(3S)-3-[(3aS)-1-氧代-2,3,3a,4,5,6-六氢-1H-苯并[de]异喹啉-2-基]-1-氮杂双环[2.2.2]辛-1-酸酯。
在再一个实施方案中,本发明提供了,优选呕吐诱发事件前不久,通过对有需要的人给予本发明的剂型,从而治疗急性及延发性呕吐的方法。
本发明的其他实施方案及优点,一部分将于下面的说明中详述,一部分可从所述说明显而易见或可通过实施本发明了解。本发明的实施方案及优点会通过后附的权利要求书具体指出的要素及组合实现并获得。应理解,前述一般性说明及后述详细说明皆仅为示例,且仅作说明用,而非如权利要求书一样限制本发明。
附图说明
纳入本说明书并作为本说明书构成部分的附图,与其说明一起示例性说明本发明的若干实施方案,以解释本发明的原理。
图1示出含有一个帕洛诺司琼的软凝胶胶囊及三片奈妥匹坦片的胶囊。
图2是描绘经口单独给予奈妥匹坦以及共同给予奈妥匹坦与帕洛诺司琼后,奈妥匹坦在人体内的药代动力学谱的二维曲线图。
图3是描绘单独给予帕洛诺司琼以及共同给予帕洛诺司琼与奈妥匹坦后,帕洛诺司琼于人体内的药代动力学谱的二维曲线图。
图4是描绘共同给予地塞米松与奈妥匹坦或者仅给予地塞米松后,地塞米松的平均血浆浓度随时间变化的二维曲线图。
图5包括两幅条形图,描绘了在单次经口给予100、300及450mg的奈妥匹坦(对于每次给药,N=2)后的第6、24、48、72及96小时,使用正电子成象术测量的纹状体及枕叶皮质内的平均NK1占据率。
具体实施方式
通过参考以下定义及本发明的优选实施方案及其中所包括的非限制性实施例的详细说明,可更容易地理解本发明。
术语的定义及使用
除非上下文另外明确指出,当本文中使用单数形式“一(a)”、“一个(an)”和“该(the)”或类似词语时,应理解它们包括复数指示物。因此,例如,提及“药物载体”,包括两种或多种这类载体的混合物,以此类推。本文中所使用的单词“或”或类似词语意指具体列表的任一成员,也包括该列表的成员的任意组合。
当在本文中使用时,术语“约”或“大约”将补偿医药工业中考虑的及医药产品固有的可变性,例如由于制造变化以及时间诱发的产品降解所导致的强度及生物可利用性的差异。该术语允许任意变动,只要所述变动在制药实践中使得评估的产品被认为与所要求保护产品的述及强度药学等价或生物等价,或者如果情况需要同时药学等价和生物等价。
本申请说明书及权利要求书全文中,词语“包含”及其变体如“含有”和“包括”意指“包括,但不限于”,而非意图排除例如其他添加剂、成分、整数或步骤。
本文所使用的术语“可药用的”意指可用于制备药物组合物的,通常安全的、无毒的并且既不是生物学不利的也不是其他不利的,不仅包括可用于人药物使用的,还包括可用于兽药使用的。此外,术语“可药用盐”指由可药用的无毒性酸制备的要给药的化合物的盐。适当的无机酸的实例是盐酸、氢溴酸、氢碘酸、硝酸、硫酸及磷酸。适当的有机酸可选自脂肪族酸、芳香族酸、羧酸及磺酸类有机酸,其实例为甲酸、乙酸、丙酸、琥珀酸、樟脑磺酸、柠檬酸、反丁烯二酸、葡糖酸、羟乙基磺酸、乳酸、苹果酸、黏液酸、酒石酸、对甲苯磺酸、乙醇酸、葡萄糖醛酸、马来酸、糠酸、谷氨酸、苯甲酸、邻胺苯甲酸、柳酸、苯乙酸、苦杏仁酸、扑酸(双羟萘酸)、甲烷磺酸、乙烷磺酸、泛酸、苯磺酸(besylate)、硬脂酸、对氨基苯磺酸、海藻酸、半乳糖醛酸等。
帕洛诺司琼的可药用盐包括盐酸帕洛诺司琼。奈妥匹坦的可药用前药包括美国专利6,593,472、6,747,026及6,806,370号描述的那些,包括奈妥匹坦的N-氧化物。这些公开文本的内容通过引用的方式纳入本文。当分子在本文中以其碱形式或盐形式被提及时,应理解也涵盖该分子的其他可药用形式。
本文所使用的“治疗有效量”指的是足以引发所需的生物反应的量。治疗有效量或剂量将取决于患者的年龄、性别及体重,以及患者的当前医疗状况。本领域技术人员能够依据这些因素和本公开之外其他因素来确定合适的剂量。
当用于治疗由高度致呕吐性化疗引起的CINV时,地塞米松的最小有效剂量已被证明为第一天经口或通过注射给予20mg,以及第二天、第三天及第四天经口或通过注射给予16mg。参见Jordan等人在THE ONCOLOGIST,2007年9月第12卷第9期第1143页至第1150页的报道。当用于治疗由中度致呕吐性化疗诱发的CINV时,地塞米松的最小有效剂量为第一天经口或通过注射给予20mg,以及第二天、第三天及第四天为0mg。
当术语“进行治疗”和“治疗”在本文中使用时,是指对患者进行以治愈、缓解、稳定或预防疾病、病理状态或病症为目标的医疗处理。这一术语包括积极治疗,即,特异性针对改善疾病、病理状态或病症的治疗;也包括病因治疗,即,针对去除相关疾病、病理状态或病症的病因的治疗。此外,这一术语还包括姑息性治疗,即,被设计用于减轻症状而非治愈疾病、病理状态或病症的治疗;预防性治疗,即,针对最小化或者部分或完全抑制相关疾病、病理状态或病症发生的治疗;以及支持性治疗,即,用以补充针对改善相关疾病、病理状态或病症的另一具体疗法的治疗。
本文所使用的术语“显著地”指的是统计显著性的水平。该统计显著性的水平可为,例如,至少p<0.05的、至少p<0.01的、至少p<0.005的或者至少p<0.001的。除非另有指明,否则统计显著性的水平为p<0.05。当在本文中表达或确定可测结果或效果时,应理解,该结果或效果是基于其相对于基线的统计显著性评估的。类似地,当在本文中描述治疗时,应理解,该治疗显示统计显著性程度的有效性。
5-HT3拮抗剂包括各种司琼类(setron),例如帕洛诺司琼、昂丹司琼、多拉司琼(dolasetron)、托比司琼(tropisetron)及格拉司琼(granisetron),及其可药用盐。优选的5-HT3拮抗剂是帕洛诺司琼,尤其是其盐酸盐。
“高度致呕吐性化疗”指的是具有高程度的致呕吐性潜力的化疗,包括基于卡氯芥(carmustine)、顺铂(cisplatin)、≥1500mg/m2的环磷酰胺、氮烯唑胺(dacarbazine)、更生霉素(dactinomycin)、氮芥(mechlorethamine)及链佐霉素的化疗。
“中度致呕吐性化疗”指的是具有中等程度的致呕吐性潜力的化疗,包括基于卡铂(carboplatin)、<1500mg/m2的环磷酰胺、>1mg/m2的阿糖胞苷(cytarabine)、正定霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊立替康(irinotecan)及奥沙利铂(oxaliplatin)的化疗。
急性呕吐指的是呕吐诱发事件后第一个24小时期间的呕吐。延发性呕吐指的是呕吐诱发事件的后第二个、第三个、第四个及第五个24小时期间的呕吐。当称治疗在延迟期内有效,应理解为意指该治疗的有效性于整个延迟期内是统计上显著的,而不管该治疗是否在延迟期的任意某个24小时期间内有效。还应理解,该方法可基于其在延迟期的任意一个24小时期间的有效性进行定义。因此,除非另有指明,否则本文所描述的治疗延迟期的恶心和/或呕吐的任意方法也可用于在呕吐诱发事件后的第二个、第三个、第四个或第五个24小时或其任意组合期间治疗恶心和/或呕吐。
当通过与范围的上限分开指定该范围的下限而得出范围时,应理解,可通过选择性结合任意一个下限变量与数学上可能的任意一个上限变量而定义该范围。
治疗方法
如上文所述,本发明以若干独特的发现为前提,提供了下列可根据本发明予以实施的独立方法,包括:
在第一主实施方案中,本发明提供了一种在连续五天期间治疗有需要的患者恶心及呕吐的方法,包括对该患者给予奈妥匹坦或其可药用盐,其量对治疗急性及延迟期的恶心及呕吐是治疗有效的,并且可进入全身循环系统,跨越血脑屏障,并在所述给药后72小时占据纹状体中至少70%的NK1受体。
在第二主实施方案中,本发明提供了用于在连续五天期间治疗有需要的患者恶心及呕吐的结合疗法,包括:
(i)于第一天对该患者给予奈妥匹坦或其可药用盐,其量对治疗急性及延迟期的恶心及呕吐是治疗有效的,并且可进入全身循环系统,跨越血脑屏障,并在所述给药后72小时占据纹状体中至少70%的NK1受体;
(ii)于第一天对该患者给予治疗有效量的对治疗急性及延迟期的恶心及呕吐有效的5-HT3拮抗剂(优选帕洛诺司琼,更优选0.5mg盐酸帕洛诺司琼形式的口服帕洛诺司琼);
(iii)于第一天对该患者给予当单独给药时对恶心及呕吐无效,但当与所述奈妥匹坦及帕洛诺司琼结合给药时对恶心及呕吐有效的第一剂地塞米松,其中所述第一剂包含单独给药时最小有效剂量的50至70%;以及
(iv)如果患者在接受高度致呕吐性化疗,于第二天、第三天及第四天对该患者给予当单独给药时对恶心及呕吐无效,但当与所述奈妥匹坦结合给药时对恶心及呕吐有效的第二剂地塞米松,其中在第二天、第三天及第四天所述第二剂包含单独给药时最小有效剂量的40至60%。
可对这些主实施方案设计多个次级实施方案。例如,可将奈妥匹坦以游离碱或其可药用盐的形式给予,但优选作为游离碱给予。此外,优选给予以游离碱的重量计约50至约500mg,约200至约400mg,优选约300mg的量的奈妥匹坦。奈妥匹坦的优选给药途径为口服。对于与NK1受体的结合而言,在给药后72小时,奈妥匹坦优选结合纹状体内至少80%或甚至85%的NK1受体。给予后96小时,奈妥匹坦优选结合少于70%、60%、50%或甚至40%的所述NK1受体。
本发明的方法对于治疗或预防由多种事件引起的恶心及呕吐全部有效,包括由中度或高度致呕吐性化疗的化疗诱发的恶心及呕吐(“CINV”)、放疗诱发的恶心及呕吐(“RINV”)及术后恶心及呕吐(“PONV”)。所述方法优选在呕吐诱发事件发生前不久(即,在该事件前不超过1或2小时)实施。所述方法可用于治疗恶心急性期期间或延迟期期间的恶心及呕吐。
由各个实施方案规定的药物可由本领域公知的任意合适的给药方案给予,但在优选的实施方案中,奈妥匹坦、5-HT3拮抗剂及类固醇经口给予。帕洛诺司琼的优选口服剂量为约0.075至约1.0mg或约0.25至约0.75mg,但优选约0.5mg。奈妥匹坦的优选口服剂量为约50至500mg或约200至约400mg,但优选约300mg。皮质类固醇优选地塞米松的优选剂量为在第一天治疗中经口或通过注射给予12mg,以及在所述治疗后第二天、第三天及第四天经口或通过注射给予8mg。
还应理解,奈妥匹坦可以以前药形式给予,在这种情况下,本发明将提供一种通过诱导奈妥匹坦的血浆水平的治疗方法,并且在每种情况下,通过给予前药诱导的奈妥匹坦的血浆水平与通过以本文所述的剂量及给药途径给予奈妥匹坦或其可药用盐所达到的水平一致。
药物组合物
可使用本文所描述的结合物来开发多种药物组合物。该组合物可由任何合适的途径给药,例如以液体或固体形式的经口、肠胃外或静脉内给药。
所述活性化合物的优选给药模式是注射和/或口服。这些组合物通常包括惰性稀释剂或可食用载体。它们可被封装于明胶胶囊中(口服用途)或压成片剂(口服或含服用途)或配制为含锭(含服用途)。对于这些目标,可将活性化合物纳入赋形剂中,并以片剂、含锭或胶囊的形式使用。药学上相容的黏合剂和/或佐剂物质可作为所述组合物的一部分被包括。
片剂、丸剂、胶囊剂、含锭等可含有任意下列成分或具有类似特性的化合物:黏合剂如微晶纤维素、黄芪胶或明胶;赋形剂如淀粉或乳糖;崩解剂如海藻酸、羟甲基淀粉钠(Primogel)或玉米淀粉;润滑剂如硬脂酸镁或氢化植物油(Sterotes);助流剂如胶体二氧化硅;甜味剂如蔗糖或糖精;或芳香剂如薄荷、柳酸甲酯或柑橘芳香剂。当剂量单元形式为胶囊时,其可含有——除上述种类的材料外——液体载体如脂肪油。此外,剂量单元形式可含有改变剂量单元的物理形式的多种其他材料,如糖衣、虫胶或其他肠内吸收剂。
所述化合物可作为酏剂、悬浮剂、糖浆、薄片、口腔崩解膜、口腔崩解片、咀嚼胶等的成分给药。糖浆可含有——除所述活性化合物外——蔗糖作为甜味剂、某些防腐剂、染料、着色剂及芳香剂。
用于注射的溶液或悬浮液可包括下列成分:无菌稀释剂如注射用水、盐水溶液、不挥发性油、聚乙二醇、甘油、丙二醇或其他合成溶剂;抗菌剂如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲剂如乙酸盐、柠檬酸盐或磷酸盐;以及用于调节等渗性的试剂如氯化钠、甘露醇及葡萄糖。可将注射制剂封装于玻璃或塑料材料的安瓿、一次性注射器或多剂量小瓶中。
结合口服剂型
如上文所述,本发明提供了可依据治疗目的容易改变并且不存在稳定性及降解问题的帕洛诺司琼与NK1拮抗剂的通用结合口服剂型。在优选的实施方案中,本发明提供了用于口服给药的胶囊,其由封装一片或多片NK1拮抗剂片剂以及一个或多个帕洛诺司琼软凝胶胶囊的硬外壳制成。成品胶囊以及封装于所述胶囊壳内的片剂及软凝胶胶囊均优选制成实时释放剂型。奈妥匹坦及卡索匹坦及其可药用盐是用于本发明的结合口服剂型的特别优选的NK1拮抗剂。
尽管所述NK1拮抗剂优选以固体片剂的形式制剂,应理解其可以以适用于口服给药的任意固体形式制剂,包括例如片剂或胶囊(硬或软凝胶)。在一个优选的实施方案中,所述NK1拮抗剂以片剂的形式制剂。所述结合剂型中含有的NK1拮抗剂单元的数目可为例如1个至10个、1个至5个或1个至3个。该结合剂型中的奈妥匹坦单元可提供以聚集体计从50至500mg、优选从100至350mg的任意量的奈妥匹坦。每个奈妥匹坦单元优选包含50至200mg、更优选100至150mg、最优选100或150mg的奈妥匹坦。
帕洛诺司琼还可以以适于口服给药的任意固体形式制剂,尽管其优选制成软凝胶胶囊。PCT公开文本WO 2008/049552中提供了适当的帕洛诺司琼软凝胶胶囊的非限制性实例,该公开文本的内容以引用的方式纳入本文。该结合剂型中帕洛诺司琼单元的数目可为,例如,1个至5个,1个至3个或仅1个。所述结合剂型中的每个帕洛诺司琼单元可提供以聚集体计从0.01至5.0mg、优选从0.1至1.0mg的任意量的帕洛诺司琼。每个帕洛诺司琼单元优选包含0.1至1.0mg的帕洛诺司琼,最优选约0.25、0.5、0.75或1.0mg的帕洛诺司琼。
图1示例性说明帕洛诺司琼与奈妥匹坦的结合口服剂型的示例性实施方案。剂型10包含两片硬外壳,包括本体20和帽22。剂型10含有一个帕洛诺司琼软凝胶胶囊30(优选含有0.5mg的帕洛诺司琼)以及三片奈妥匹坦片剂40(每片优选含有100mg的奈妥匹坦)。
硬外壳
本发明的硬外壳可由在胃液中溶解的任意可药用材料作成。优选的硬外壳用材料包括,例如,明胶、纤维素、淀粉或羟丙基甲基纤维素(HPMC)。在本发明的一个具体实施方案中,所述硬外壳具有最大氧渗透率。优选地,所述氧渗透率低于约1.0×10-3、5.0×10-4、1.0×10-4、5.0×10-5或甚至2.0×10-5mL·cm/(cm2·24hr.atm)。
硬外壳可为连续结构。或者,硬外壳可为两片式硬胶囊。
软凝胶胶囊
用于帕洛诺司琼的软凝胶胶囊优选包含软外壳以及包含盐酸帕洛诺司琼的内部液体填料组合物。PCT公开文本WO 2008/049552提供了合适的帕洛诺司琼软凝胶胶囊的非限制性实例,该公开文本的内容通过引用的方式纳入本文。
所述软凝胶胶囊的软外壳可含有在胃液中溶解的任意种类的材料。优选的软外壳用材料包括,例如,明胶、纤维素、淀粉或羟丙基甲基纤维素(HPMC)。所述软凝胶胶囊还可包含壳赋形剂如甘油、山梨糖醇及着色剂/遮光剂如二氧化钛。所述软凝胶胶囊还可包含溶剂如纯化水。在本发明的一个具体实施方案中,外壳具有最大氧渗透率,优选不超过1.0×10-3、5.0×10-4、1.0×10-4、5.0×10-5或甚至2.0×10-5mL·cm/(cm2·24hr.atm)。合适的软凝胶胶囊包括由Catalent Pharma Solutions制造的1.5-卵形明胶胶囊壳。
液体填料优选主要由一种或多种50wt.%至99wt.%,优选75wt.%至98wt.%的量的亲脂性成分构成。优选的亲脂性成分包括,例如,脂肪酸的单甘油酯及二甘油酯,尤其包括癸酸的单甘油酯及二甘油酯。所述液体填料也可含有优选1至15wt.%、更优选2至10wt.%的量的甘油。在一个优选的实施方案中,所述壳与所述内部填料组合物两者皆包含甘油。于另一优选的实施方案中,所述液体填料包含约0.25、0.50、0.75mg或更多的盐酸帕洛诺司琼形式的帕洛诺司琼。
所述填料组合物可包含多种工具以促进帕洛诺司琼由所述剂型传输至胃肠道的胃肠液中,从而使帕洛诺司琼可更容易被吸收到血流中。例如,所述液体填料组合物可含有表面活性剂,最好为0.1wt.%至6wt.%,0.5wt.%至5wt.%,或1.0wt.%至3.0wt.%的量。所述液体填料组合物优选包含超过0.1、0.5或1.0wt.%的表面活性剂,以及低于10、8、5、4或甚至4wt.%的表面活性剂。特别优选的表面活性剂是聚油酸甘油酯。
或者或另外,用于液体填充胶囊的转运工具可包含水,所述水与所述赋形剂基质中的其他液体组分形成单相或微乳。所述液体填料组合物优选包含0.05wt.%至30wt.%的水,1wt.%至20wt.%的水,或2wt.%至10wt.%的水。所述液体填料优选包含超过0.1、0.5或1.0wt.%的水,以及低于20、15、10、8或5wt.%的水。
所述填料组合物中优选存在0.01至10.0wt.%、0.05至5.0wt.%、或0.1wt.%至2.0wt.%的量的活性药剂,优选盐酸帕洛诺司琼。或者,已经发现特别稳定的配方,其中帕洛诺司琼的浓度超过0.3%,所述浓度优选不大于1wt.%。
片剂
本发明的片剂可包括20至95wt.%的NK1拮抗剂(优选奈妥匹坦),优选包含60至80wt.%的奈妥匹坦。此外,所述片剂可含有稀释剂、崩解剂、表面活性剂、黏合剂、助流剂和/或润滑剂。在一个具体的实施方案中,所述片剂包含5至25wt.%的微晶纤维素。所述微晶纤维素可作为稀释剂及崩解剂起作用,并且优选占所述片剂的15wt.%。另一合适的崩解剂为交联羧甲基纤维素钠(sodium croscaramellose),其可以以1至5wt.%,优选2wt.%,的量存在于所述片剂中。
用在所述片剂中合适的黏合剂有聚乙烯基吡咯烷酮,且可以以所述片剂的1至10wt.%,优选5wt.%,的量存在于所述片剂中。用在所述片剂中合适的助流剂有胶体二氧化硅,其可以以2wt.%的量存在于所述片剂中。用在所述片剂中合适的润滑剂包括硬脂酰富马酸钠及硬脂酸镁,其可以分别以0.7wt.%及0.35wt.%的量存在于所述片剂中。
结合口服剂型的应用
本发明进一步提供了一种治疗呕吐的方法,包括对患有呕吐的患者或具有患呕吐的风险的患者经口给予本发明的剂型。在其他实施方案中,本发明提供了通过给予一种或多种本文所述的剂型来治疗呕吐的方法。所述剂型优选在呕吐诱发事件前不久(即,所述事件前不超过2小时)给药。所述呕吐可为急性期呕吐(即,呕吐诱发事件后约24小时内发生的呕吐),或迟发性呕吐(即,在所述急性期之后,但在呕吐诱发事件后7天、6天、5天或4天之内发生的呕吐)。所述呕吐可包括由中度或高度致呕吐性化疗引起的化疗诱发的恶心及呕吐(“CINV”)、放疗诱发的恶心及呕吐(“RINV”)或术后恶心及呕吐(“PONV”)。
实施例
给出下述实施例以向本领域普通技术人员提供如何制备并评估本文所要求保护的化合物的完整公开及说明,下述实施例纯粹是为了对本发明的示例而非意图限制发明人所认为其发明的范围。已经努力确保数值(如,量、温度等)的准确性,但不可避免存在某些误差及偏差。除非另有指明,份数为重量份数,温度以℃为单位或者为室温,并且压力处于或接近大气压。
实施例1:口服剂型的制备
在一个优选的实施方案中,所述结合物以胶囊口服剂型给药,其中所述胶囊封装一个或多个帕洛诺司琼的软凝胶胶囊以及一片或多片奈妥匹坦的硬片。下表1描述适于包括在这类硬外壳中的含有0.5mg的帕洛诺司琼的软凝胶胶囊的代表性配方。
表1:代表性软凝胶配方
1相当于0.50mg游离碱
2胶囊壳的定量组合物为Catalent Pharma Solutions专有
下表2描述适于包括在硬壳中的含有100mg的奈妥匹坦的片剂的代表性配方。
表2:代表性片剂配方
组分 | 大约量(mg/片) | 功能 |
奈妥匹坦,经研磨的 | 100 | 活性剂 |
微晶纤维素pH 101 | 20.5 | 稀释剂及崩解剂 |
蔗糖月桂酸酯 | 10.0 | 表面活性剂 |
聚乙烯基吡咯烷酮K30 | 7.0 | 黏合剂 |
交联羧甲基纤维素钠 | 3.0 | 崩解剂 |
胶体二氧化硅 | 3.0 | 助流剂 |
硬脂基富马酸钠 | 1.0 | 润滑剂 |
硬脂酸镁 | 0.5 | 润滑剂 |
总重 | 145mg |
实施例2:结合剂型的药代动力学
目的
在健康志愿者体内检查了帕洛诺司琼对奈妥匹坦的药代动力学(PK)的效应以及奈妥匹坦对帕洛诺司琼的PK的效应。
方法
进行了随机的开放三路交叉研究。每个受试者参与3个治疗期,每个治疗期约持续12天(第-1天至第11天)。所述治疗期由不少于14天的间歇期(任意两个连续治疗期的第1天之间)分隔。
研究了下述治疗:
治疗A:以3个150mg的胶囊单次经口给予奈妥匹坦450mg。
治疗B:以3个150mg奈妥匹坦胶囊和随后1个0.75mg帕洛诺司琼胶囊同时经口给予帕洛诺司琼0.75mg和奈妥匹坦450mg。
治疗C:以一个0.75mg胶囊单次经口给予帕洛诺司琼0.75mg。
给药在禁食状态下进行。受试者禁食过夜约10小时。但至给药前1小时可饮水。给药4小时后可进食,在给药1小时后可随意饮水。
受试者在直立状态进行给药。受试者给药后保持直立状态4小时。所述胶囊和250mL室温自来水一同整体吞下。进行重复PK血液取样(用于奈妥匹坦和/或帕洛诺司琼)。
结果
评估奈妥匹坦与帕洛诺司琼的主PK变量是观察到的最大血浆浓度(Cmax);从时间零至最后可量化取样的时间点(t)的所述血浆浓度相对时间曲线下的面积(AUC0-t);以及从时间零至无限大(AUC0-inf)所述血浆浓度相对时间曲线下的面积。所评估的次PK变量是终末消除半衰期(t1/2,z),以及观察到最大血浆浓度的时间(tmax)。结果示于表3及表4以及图2及图3中。
表3:奈妥匹坦药代动力学参数总结
除tmax及t1/2显示中值及范围以外,其他参数均显示平均值及标准差。
由下表4中可知,与单次给予的帕洛诺司琼相比,帕洛诺司琼与奈妥匹坦组合给予显示更佳的药代动力学谱,如更大的AUC,更高的Cmax,更短的tmax(将帕洛诺司琼与奈妥匹坦组合给予的后,中值tmax缩短0.5小时),以及更长的t1/2,z。
表4:帕洛诺司琼药代动力学参数总结
除tmax及t1/2显示中值及范围以外,其他参数均显示平均值及标准差。
实施例3:奈妥匹坦+地塞米松药物相互作用研究
在此研究中,评估了奈妥匹坦对经口给予的地塞米松的药代动力学的效应。这是使用不完全拉丁方(Latin Square)设计的随机的开放三周期交叉研究,其中对受试者仅给予地塞米松,或随地塞米松经口给予奈妥匹坦100mg、300mg或450mg。仅在第1天经口给予奈妥匹坦。每一治疗的地塞米松方案为第1天口服20mg,第2至4天每12小时口服8mg。19名受试者(12名男性,7名女性)完成了本研究(即,全部3个治疗期)。
当地塞米松与奈妥匹坦共同给予时,地塞米松的平均血浆浓度更高(图4)。此增长似乎依赖奈妥匹坦的存在。
当分别与100、300及450mg的奈妥匹坦共同给药时,地塞米松的AUC0-24(第1天)是单独给药的1.5倍、1.7倍及1.8倍。当分别与100、300及450mg的奈妥匹坦共同给药时,地塞米松的AUC24-36(第2天)是单独给药的2.1倍、2.4倍及2.6倍,且AUC84-108及AUC84-inf(第4天)是单独给药的1.7倍、2.4倍及2.7倍。地塞米松在第1天的Cmax仅受到与奈妥匹坦共同给药的轻微影响(分别与100及300mg的奈妥匹坦共同给药时,是单独给药的1.1倍;与450mg的奈妥匹坦共同给药时,是单独给药的1.2倍)。在第2天及第4天,给予奈妥匹坦的受试者的Cmax是单独给药的大约1.7倍。分别与100、300及450mg的奈妥匹坦共同给药时,地塞米松在第2至4天的Cmin是单独给药的大约2.8倍、4.3倍及4.6倍。这清楚地表明,共同给予奈妥匹坦与地塞米松可增加地塞米松的生物可利用性,并且可提供更佳的地塞米松治疗窗口。
实施例4:奈妥匹坦的PET受体占据率研究
这是使用11C-GR205171作为示踪剂在接受单次奈妥匹坦(100、300或450mg)的6名(每剂量水平2名)健康男性志愿者体内进行的随机、开放标记的正电子成象术(PET)研究,以研究人脑中NK1受体占据程度,以及确定奈妥匹坦的血浆浓度与NK1受体占据率(RO)之间的关系。
在6名受试者中的3人中,纹状体、枕叶皮质、额叶皮质及前扣带皮层达到接近预期Cmax(给药后6小时)的预想高NK1-RO(90%或更高),其中1人接受300mg的奈妥匹坦,2人接受450mg的奈妥匹坦,均以单次口服的形式。
所有给药均显示相对长时间的NK1受体锁定,且随着时间的下滑是剂量依赖的。在100mg剂量组中,在给药96小时后,6个区域中的4个仍具有超过70%的平均NK1-RO。在最高剂量组(450mg)中,在给药96小时后,6个区域中的5个仍具有80%或更高的平均NK1-RO。给药组(100mg、300mg及450mg)的对比结果显示,随着奈妥匹坦剂量的增加,NK1-RO具有持续但小量的增加(图5)。
实施例5:临床有效性研究
与仅给予帕洛诺司琼及地塞米松比较,II期试验评估了与帕洛诺司琼及地塞米松合用的三种单次剂量的奈妥匹坦,以获得在CINV患者人群中结合口服帕洛诺司琼使用的奈妥匹坦的剂量范围信息。
本研究的目的是,对结合口服帕洛诺司琼并随地塞米松给予的三种单次剂量的奈妥匹坦与随地塞米松(无奈妥匹坦)给予的仅口服帕洛诺司琼比较在预防高度致呕吐性化疗(HEC)诱发的恶心及呕吐中的有效性及安全性。本研究包括随静脉注射(IV)昂丹司琼及地塞米松给予FDA批准的口服阿瑞匹坦方案,作为用于探索性目的的有效比较物。在此研究中的每个适用治疗组中,均使用FDA批准的口服帕洛诺司琼0.5mg剂量。
此为多中心、随机、双盲、双安慰剂、平行组、分层研究。将合格的患者随机(由性别分层)分配至下述治疗组的一个中:
第1组:第1天口服0.5mg的帕洛诺司琼(随口服地塞米松标准方案:第1天20mg,从第2至4天8mg BID)
第2组:第1天口服100mg的奈妥匹坦+口服0.5mg的帕洛诺司琼(随口服地塞米松调整方案*:第1天12mg,第2至4天每天8mg)
第3组:第1天口服200mg的奈妥匹坦+口服0.5mg的帕洛诺司琼(随口服地塞米松调整方案*:第1天12mg,第2至4天每天8mg)
第4组:第1天口服300mg的奈妥匹坦+口服0.5mg的帕洛诺司琼(随口服地塞米松调整方案*:第1天12mg,第2至4天每天8mg)
第5组:口服125mg的阿瑞匹坦+IV昂丹司琼32mg(都在第1天),随后第2天及第3天口服80mg的阿瑞匹坦(全部随口服地塞米松调整方案*:第1天12mg,第2至4天每天8mg)
此外,基于Grunberg等人在Support Cancer Care(2009)17:589-594中报道的结果,将第6组加入分析中,用于比较的目的:
第6组:口服285mg的阿瑞匹坦+口服20mg的地塞米松+0.2mg的帕洛诺司琼(i.v.)(都在第1天),随后口服80mg的阿瑞匹坦。
主有效性指标为在高度致呕吐性化疗开始后120小时内的完全反应率(定义为无致呕吐事件,无援救药物)。次有效性指标为:
0至24小时间隔(急性期);以及25至120小时间隔(延迟期)的完全反应;
完全保护(定义为无呕吐,无援救治疗,无显著恶心);全部控制(定义为无呕吐,无援救治疗及无恶心);无恶心(最大VAS<5mm);无显著恶心(最大VAS<25mm);无援救药物;无呕吐。对于0至120小时的间隔(全部期间)、急性期及延迟期评价这些指标。
至第一次致呕吐事件的时间;至第一次援救治疗的时间;至治疗失败的时间(基于至第一次致呕吐事件和第一次援救药物中先出现的那个的时间);
全部期间、急性期及延迟期恶心的严重性;患者对由每次间隔24小时的借助VAS的抗呕吐治疗的综合满意度。
完全反应率总结在表5中。在开始给予顺铂后0至120小时内完全反应的患者的百分比,在仅帕洛诺司琼组中为76.5%,在分别给予100mg、200mg及300mg的奈妥匹坦的组中为87.4%、87.6%及89.6%。与仅帕洛诺司琼组的差距大于10%(10.9%至13.2%)。奈妥匹坦的全部剂量均在统计上优于仅帕洛诺司琼(对于奈妥匹坦300mg结合物组,p值=0.004)。
表5:全部期间、急性期及延迟期中MFAS人群的完全反应率
(*)p值来自逻辑回归分析,阿瑞匹坦p值来自事后逻辑回归分析
表6总结了主、次指标的结果。在全部期间,76.5%的仅帕洛诺司琼组的患者未发生呕吐,而在100mg、200mg及300mg的奈妥匹坦结合物组中分别87.4%、87.6%及91.1%的患者未发生呕吐(对于全部剂量,p<0.05)。
表6:次有效性结果的总结:MFAS人群患者的百分比
*与仅帕洛诺司琼相比,p值<0.05;阿瑞匹坦比较p值通过事后分析计算**如Grunberg等人在Support Cancer Care(2009)17:589-594中所报导的
实施例7:阿瑞匹坦给药方案的比较结果
下表8报告了对于阿瑞匹坦给药方案观察到的结果,如FDA批准的阿瑞匹坦处方信息所指出的,所述结果表明阿瑞匹坦对恶心无有意义的效果。表7报告了所述给药方案:
表7
表8:
接受高度致呕吐性化疗的患者响应研究1—第1轮——的治疗组及治疗期的患者百分比
接受顺铂、研究药物且进行至少一种治疗后有效性评估的患者(年龄超过18岁)的数量
全部期间:顺铂治疗后0至120小时
急性期:顺铂治疗后0至24小时
II延迟期:顺铂治疗后25至120小时
*当对多重比较调整时,无统计显著性
在整个本申请中,引用了多篇出版物。这些出版物的公开通过引用的方式全文纳入本申请,以更完全揭示本发明所属技术领域的现状。本领域技术人员会明了,可对本发明作出多种修改及变化而不悖离本发明的范围及精神。通过考虑本说明书并且实行本文所公开的本发明,本领域技术人员可明了本发明的其他实施方案。应认为本说明书及实施例仅为实例,而本发明的真实范围及精神由后附的权利要求书给出。
Claims (6)
1.一种连续五天治疗有需要的患者的恶心及呕吐的方法,包括:
a)于第一天对该患者给予治疗有效量的奈妥匹坦或其可药用盐,其对治疗呕吐的急性及延迟期的恶心及呕吐有效,并且进入系统循环,跨越血脑屏障,并在给药后72小时占据纹状体中至少70%的NK1受体;
b)于第一天对所述患者给予治疗有效量的5-HT3拮抗剂或其可药用盐,其对治疗急性及延迟期的恶心及呕吐有效;以及
c)于第一天对该患者给予当单独给药时对恶心及呕吐无效,但当与所述奈妥匹坦结合给药时对恶心及呕吐有效的第一剂地塞米松,其中所述第一剂包含单独给药时最小有效剂量的50至70%。
2.一种连续五天治疗有需要的患者的恶心及呕吐的方法,包括对所述患者给予治疗有效量的奈妥匹坦或其可药用盐,其对治疗呕吐的急性及延迟期的恶心及呕吐有效,并且进入系统循环,跨越血脑屏障,并在给药后72小时占据纹状体中至少70%的NK1受体。
3.一种在由中度或高度致呕吐性化疗引起CINV的急性和/或延迟期治疗有需要的人受试者的恶心及呕吐的方法,包括在所述化疗之前,给予治疗有效量的奈妥匹坦或其可药用盐以及治疗有效量的帕洛诺司琼或其可药用盐。
4.一种包括帕洛诺司琼与NK1拮抗剂或其可药用盐或前药的结合物的口服剂型,包括:
a)外壳;
b)一个或多个封装在所述外壳内的NK1拮抗剂单元,每个单元包含所述奈妥匹坦或其可药用盐或前药以及一种或多种可药用赋形剂;以及
c)一个或多个封装在所述外壳内的帕洛诺司琼单元,每个单元包含所述帕洛诺司琼或其可药用酯或前药以及一种或多种可药用赋形剂;
其中,所述剂型包含不超过3重量%的量的(3S)-3-[(3aS)-1-氧代-2,3,3a,4,5,6-六氢-1H-苯并[de]异喹啉-2-基]-1-氮杂双环[2.2.2]辛-1-酸酯。
5.一种口服胶囊剂型,包括:
a)外壳;
b)一片或多片封装在所述外壳内的片剂,其各自包含NK1拮抗剂或其可药用盐或前药以及一种或多种可药用的赋形剂;以及
c)一个或多个封装在所述外壳内的软凝胶胶囊,其各自包含帕洛诺司琼或其可药用的酯或前药以及一种或多种可药用的赋形剂;
其中,所述剂型包括不超过3重量%的量的(3S)-3-[(3aS)-1-氧代-2,3,3a,4,5,6-六氢-1H-苯并[de]异喹啉-2-基]-1-氮杂双环[2.2.2]辛-1-酸酯。
6.一种治疗呕吐的方法,包括对有需要的人给予如权利要求4或5所述的剂型。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26247009P | 2009-11-18 | 2009-11-18 | |
US61/262,470 | 2009-11-18 | ||
US38270910P | 2010-09-14 | 2010-09-14 | |
US61/382,709 | 2010-09-14 | ||
CN2010800521070A CN102655864A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010800521070A Division CN102655864A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107050455A true CN107050455A (zh) | 2017-08-18 |
CN107050455B CN107050455B (zh) | 2020-09-29 |
Family
ID=43608757
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610795827.5A Active CN106421793B (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN201610795817.1A Active CN107050455B (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN201510046972.9A Pending CN104856998A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN201510047631.3A Pending CN104856999A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN201610797549.7A Pending CN106512010A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN2010800521070A Pending CN102655864A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610795827.5A Active CN106421793B (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510046972.9A Pending CN104856998A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN201510047631.3A Pending CN104856999A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN201610797549.7A Pending CN106512010A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
CN2010800521070A Pending CN102655864A (zh) | 2009-11-18 | 2010-11-18 | 用于治疗中枢介导的恶心及呕吐的组合物及方法 |
Country Status (39)
Country | Link |
---|---|
US (1) | US12042494B2 (zh) |
EP (3) | EP2722044B1 (zh) |
JP (1) | JP5890780B2 (zh) |
KR (1) | KR101615108B1 (zh) |
CN (6) | CN106421793B (zh) |
AP (1) | AP3083A (zh) |
AU (1) | AU2010320598B2 (zh) |
BR (1) | BR112012011485B1 (zh) |
CA (1) | CA2778301C (zh) |
CL (1) | CL2012001276A1 (zh) |
CO (1) | CO6551693A2 (zh) |
CR (1) | CR20120216A (zh) |
CU (1) | CU24048B1 (zh) |
CY (1) | CY1118062T1 (zh) |
DK (2) | DK2722045T3 (zh) |
DO (1) | DOP2012000138A (zh) |
EA (1) | EA026815B1 (zh) |
EC (1) | ECSP12011907A (zh) |
ES (4) | ES2595077T3 (zh) |
GE (1) | GEP20156226B (zh) |
GT (1) | GT201200156A (zh) |
HK (2) | HK1214148A1 (zh) |
HR (3) | HRP20140759T1 (zh) |
HU (1) | HUE029677T2 (zh) |
IL (1) | IL219576A (zh) |
LT (1) | LT2722045T (zh) |
MA (1) | MA33810B1 (zh) |
MX (1) | MX2012005347A (zh) |
MY (1) | MY159393A (zh) |
NI (1) | NI201200090A (zh) |
NZ (1) | NZ599439A (zh) |
PE (1) | PE20121483A1 (zh) |
PL (3) | PL2722045T3 (zh) |
PT (2) | PT2361090E (zh) |
RS (2) | RS53491B1 (zh) |
SI (2) | SI2361090T1 (zh) |
SM (1) | SMT201400112B (zh) |
TN (1) | TN2012000170A1 (zh) |
WO (1) | WO2011061622A1 (zh) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5890780B2 (ja) | 2009-11-18 | 2016-03-22 | ヘルシン ヘルスケア ソシエテ アノニム | 中枢を介する悪心および嘔吐を治療するための組成物および方法 |
EP2722045B1 (en) | 2009-11-18 | 2016-07-06 | Helsinn Healthcare SA | Compositions for treating centrally mediated nausea and vomiting |
ES2672099T3 (es) | 2011-07-04 | 2018-06-12 | Irbm - Science Park S.P.A. | Antagonistas del receptor NK-1 para el tratamiento de la neovascularización corneal |
DK2744497T3 (en) * | 2011-10-18 | 2016-08-01 | Helsinn Healthcare Sa | THERAPEUTIC COMBINATION OF netupitant AND palonosetron |
US8426450B1 (en) | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
US9403772B2 (en) | 2011-11-29 | 2016-08-02 | Helsinn Healthcare Sa | 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator |
CN103520725B (zh) * | 2012-07-05 | 2017-10-24 | 海思科医药集团股份有限公司 | 一种治疗呕吐的药物组合物 |
CN106902086B (zh) * | 2015-12-23 | 2020-10-20 | 江苏恒瑞医药股份有限公司 | 一种包含奈妥匹坦的固体组合物 |
GB201618425D0 (en) * | 2016-11-01 | 2016-12-14 | Acacia Pharma Ltd | method |
GB201702250D0 (en) | 2017-02-10 | 2017-03-29 | Acacia Pharma Ltd | Method |
CN108721214B (zh) * | 2017-04-14 | 2020-06-16 | 和龙 | 奈妥吡坦和帕洛诺司琼复方纳米粒溶液、纳米粒及制备方法和用途 |
CN108853010A (zh) * | 2017-05-15 | 2018-11-23 | 和龙 | 奈妥吡坦环糊精包合物、复方组合制剂及其制备方法和用途 |
CN109200018A (zh) * | 2017-07-04 | 2019-01-15 | 南京诺瑞特医药科技有限公司 | 含有奈妥吡坦的微乳制剂 |
KR20200088346A (ko) * | 2017-11-17 | 2020-07-22 | 반다 파마슈티칼즈, 인코퍼레이티드. | 트라디피탄트를 이용한 위장 질환의 치료 방법 |
EP3746078A4 (en) * | 2018-02-02 | 2021-11-17 | Eustralis Pharmaceuticals Limited (Trading as Pressura Neuro) | ORAL FORMULATIONS AND USES THEREOF |
EP4385497A1 (en) | 2022-12-12 | 2024-06-19 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Antioxidant-free fixed dose combination of netupitant and palonosetron |
WO2024126398A1 (en) | 2022-12-12 | 2024-06-20 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Fixed dose combination comprising netupitant and palonosetron |
EP4385500A1 (en) | 2022-12-12 | 2024-06-19 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Fixed dose combination comprising netupitant and palonosetron |
WO2024126408A1 (en) | 2022-12-12 | 2024-06-20 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Antioxidant-free fixed dose combination of netupitant and palonosetron |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101330905A (zh) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | 冻干方法和由此获得的产品 |
WO2009005673A1 (en) * | 2007-06-28 | 2009-01-08 | Schering Corporation | Anti-igf1r |
WO2009079587A2 (en) * | 2007-12-18 | 2009-06-25 | Schering Corporation | Biomarkers for sensitivity to anti-igf1r therapy |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL96486A (en) | 1989-11-28 | 1995-03-30 | Syntex Inc | Preparation tricyclic compounds and pharmaceutical preparations containing them |
US5510486A (en) | 1994-07-26 | 1996-04-23 | Syntex (U.S.A.) Inc. | Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one |
US6297395B1 (en) | 1995-11-10 | 2001-10-02 | The Secretary Of State For Defence In Her Brittanic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland | Calixarenes and their use for sequestration of metals |
ATE496032T1 (de) | 1999-02-24 | 2011-02-15 | Hoffmann La Roche | 4-phenylpyridinderivate und deren verwendung als nk-1 rezeptorantagonisten |
RS50932B (sr) | 2000-07-14 | 2010-08-31 | F. Hoffmann-La Roche Ag. | N-oksidi kao prolekovi 4-fenil-piridinskih derivata koji su antagonisti nk1 receptora |
CA2431397C (en) | 2000-12-14 | 2007-05-01 | F. Hoffmann-La Roche Ag | Self emulsifying lipid matrix (selm) |
WO2004045615A1 (en) | 2002-11-15 | 2004-06-03 | Helsinn Healthcare Sa | Palonosetron for the treatment of chemotherapy-induced emesis |
JO2735B1 (en) | 2003-01-30 | 2013-09-15 | هيلسين هيلث كير أس ايه. | Liquid pharmaceutical formations of balloonosterone |
TWI355936B (en) | 2003-02-18 | 2012-01-11 | Helsinn Healthcare Sa | Uses of palonosetron hydrochloride |
WO2004091622A1 (en) * | 2003-04-08 | 2004-10-28 | Progenics Pharmaceuticals, Inc. | The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome |
KR20070094666A (ko) | 2005-02-25 | 2007-09-20 | 에프. 호프만-라 로슈 아게 | 약제 물질 분산성이 향상된 정제 |
US7479312B2 (en) | 2005-07-07 | 2009-01-20 | Konica Minolta Opto, Inc. | Retardation film, polarizing plate, and liquid crystal display device |
MEP6808A (xx) * | 2006-02-23 | 2010-02-10 | Lundbeck & Co As H | Priperidinoilpirodolini agonisti receptora menalokortina tipa 4 |
EA016455B1 (ru) * | 2006-10-24 | 2012-05-30 | Хелсинн Хелткэр С.А. | Мягкие капсулы, содержащие палоносетрона гидрохлорид, имеющие улучшенную стабильность и биологическую доступность |
JP5890780B2 (ja) | 2009-11-18 | 2016-03-22 | ヘルシン ヘルスケア ソシエテ アノニム | 中枢を介する悪心および嘔吐を治療するための組成物および方法 |
-
2010
- 2010-11-18 JP JP2012539433A patent/JP5890780B2/ja active Active
- 2010-11-18 PT PT108053018T patent/PT2361090E/pt unknown
- 2010-11-18 PT PT141516831T patent/PT2722045T/pt unknown
- 2010-11-18 HU HUE14151683A patent/HUE029677T2/hu unknown
- 2010-11-18 MY MYPI2012002073A patent/MY159393A/en unknown
- 2010-11-18 EP EP14151678.1A patent/EP2722044B1/en active Active
- 2010-11-18 AP AP2012006278A patent/AP3083A/xx active
- 2010-11-18 CN CN201610795827.5A patent/CN106421793B/zh active Active
- 2010-11-18 RS RSP20140423 patent/RS53491B1/en unknown
- 2010-11-18 CA CA2778301A patent/CA2778301C/en active Active
- 2010-11-18 PL PL14151683T patent/PL2722045T3/pl unknown
- 2010-11-18 RS RS20160833A patent/RS55206B1/sr unknown
- 2010-11-18 PL PL10805301T patent/PL2361090T3/pl unknown
- 2010-11-18 ES ES14151683.1T patent/ES2595077T3/es active Active
- 2010-11-18 AU AU2010320598A patent/AU2010320598B2/en active Active
- 2010-11-18 CN CN201610795817.1A patent/CN107050455B/zh active Active
- 2010-11-18 KR KR1020127015676A patent/KR101615108B1/ko active IP Right Grant
- 2010-11-18 EA EA201290356A patent/EA026815B1/ru active Protection Beyond IP Right Term
- 2010-11-18 GE GEAP201012752A patent/GEP20156226B/en unknown
- 2010-11-18 CN CN201510046972.9A patent/CN104856998A/zh active Pending
- 2010-11-18 EP EP14151676.5A patent/EP2727590B1/en active Active
- 2010-11-18 PL PL14151678T patent/PL2722044T3/pl unknown
- 2010-11-18 CN CN201510047631.3A patent/CN104856999A/zh active Pending
- 2010-11-18 WO PCT/IB2010/003106 patent/WO2011061622A1/en active Application Filing
- 2010-11-18 ES ES14151676.5T patent/ES2559475T3/es active Active
- 2010-11-18 BR BR112012011485-9A patent/BR112012011485B1/pt active IP Right Grant
- 2010-11-18 CN CN201610797549.7A patent/CN106512010A/zh active Pending
- 2010-11-18 NZ NZ599439A patent/NZ599439A/en unknown
- 2010-11-18 DK DK14151683.1T patent/DK2722045T3/en active
- 2010-11-18 LT LTEP14151683.1T patent/LT2722045T/lt unknown
- 2010-11-18 SI SI201030688T patent/SI2361090T1/sl unknown
- 2010-11-18 DK DK10805301.8T patent/DK2361090T3/da active
- 2010-11-18 EP EP10805301.8A patent/EP2361090B1/en active Active
- 2010-11-18 CN CN2010800521070A patent/CN102655864A/zh active Pending
- 2010-11-18 ES ES14151678.1T patent/ES2623503T3/es active Active
- 2010-11-18 ES ES10805301.8T patent/ES2494015T3/es active Active
- 2010-11-18 MX MX2012005347A patent/MX2012005347A/es active IP Right Grant
- 2010-11-18 PE PE2012000686A patent/PE20121483A1/es active IP Right Grant
- 2010-11-18 SI SI201031291T patent/SI2722045T1/sl unknown
-
2012
- 2012-04-13 TN TNP2012000170A patent/TN2012000170A1/en unknown
- 2012-04-26 CR CR20120216A patent/CR20120216A/es unknown
- 2012-05-03 IL IL219576A patent/IL219576A/en active IP Right Grant
- 2012-05-10 NI NI201200090A patent/NI201200090A/es unknown
- 2012-05-15 DO DO2012000138A patent/DOP2012000138A/es unknown
- 2012-05-16 CL CL2012001276A patent/CL2012001276A1/es unknown
- 2012-05-17 EC ECSP12011907 patent/ECSP12011907A/es unknown
- 2012-05-18 CO CO12082329A patent/CO6551693A2/es not_active Application Discontinuation
- 2012-05-18 CU CU2012000078A patent/CU24048B1/es active IP Right Grant
- 2012-05-18 GT GT201200156A patent/GT201200156A/es unknown
- 2012-06-11 MA MA34953A patent/MA33810B1/fr unknown
-
2014
- 2014-08-11 HR HRP20140759AT patent/HRP20140759T1/hr unknown
- 2014-08-18 SM SM201400112T patent/SMT201400112B/xx unknown
-
2016
- 2016-02-24 HK HK16102110.3A patent/HK1214148A1/zh unknown
- 2016-02-24 HK HK16102109.6A patent/HK1214147A1/zh unknown
- 2016-10-05 CY CY20161100991T patent/CY1118062T1/el unknown
- 2016-10-05 HR HRP20161277TT patent/HRP20161277T1/hr unknown
-
2017
- 2017-03-14 HR HRP20170419TT patent/HRP20170419T1/hr unknown
-
2022
- 2022-12-16 US US18/082,737 patent/US12042494B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101330905A (zh) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | 冻干方法和由此获得的产品 |
WO2009005673A1 (en) * | 2007-06-28 | 2009-01-08 | Schering Corporation | Anti-igf1r |
WO2009079587A2 (en) * | 2007-12-18 | 2009-06-25 | Schering Corporation | Biomarkers for sensitivity to anti-igf1r therapy |
Non-Patent Citations (4)
Title |
---|
BRENDAN JOHNSON ET AL: "Impact of casopitant, a novel NK-1 antagonist,on the pharmacokinetics of ondansetron and dexamethasone", 《SUPPORT CARE CANCER》 * |
DIEMUNSCH P. ET AL: "Neurokinin-1 Receptor Antagonists in the Prevention of Posioperative Nausea and Vomiting", 《BRITISH JOURNAL OF ANAESTHESIA》 * |
EDWAD B.ET AL: "new approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations", 《THE CANCER JOURNAL》 * |
REDDY G,KESAVA ET AL: "Novel neurokinin-1 antagonists as antiemeticsfor the treatment of chemotherapy-induced emesis", 《SUPPORTIVE CANCER THERAPY》 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107050455A (zh) | 用于治疗中枢介导的恶心及呕吐的组合物及方法 | |
TWI595873B (zh) | 用於治療中樞誘發噁心及嘔吐之組成物及方法 | |
CN100502858C (zh) | 柚皮素及其衍生物用于制备抗心脑系统疾病产品的用途 | |
CN106413717A (zh) | 药物组合物 | |
US20070004792A1 (en) | Method of treating hypertension with a very low dose of chlorthalidone | |
TW200831072A (en) | Non-steroidal anti-inflammatory drugs for cough | |
WO2022103638A1 (en) | Cannabinoids in the treatment of autism spectrum disorder | |
CN109310691A (zh) | 用于快速开始抗抑郁作用的给药方案 | |
WO2020214791A1 (en) | Celecoxib compositions and methods for their use | |
RU2540509C1 (ru) | Лекарство | |
UA147360U (uk) | Спосіб симптоматичного лікування болю | |
RU2452476C2 (ru) | Производные 1-аминоалкилциклогексана для лечения и предупреждения потери слуха |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information | ||
CB02 | Change of applicant information |
Address after: Lugano Switzerland - Pazalo Applicant after: Heersen health care Co Ltd Address before: Lugano Switzerland - Pazalo Applicant before: Helsinn Healthcare SA |
|
GR01 | Patent grant | ||
GR01 | Patent grant |